Articles de revues : « Differentiation checkpoint »

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Polesskaya, Anna, et Michael A. Rudnicki. « A MyoD-Dependent Differentiation Checkpoint ». Developmental Cell 3, n^o 6 (décembre 2002) : 757–58. http://dx.doi.org/10.1016/s1534-5807(02)00372-6.

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Munz, Barbara, Eberhard Hildt, Matthew L. Springer et Helen M. Blau. « RIP2, a Checkpoint in Myogenic Differentiation ». Molecular and Cellular Biology 22, n^o 16 (15 août 2002) : 5879–86. http://dx.doi.org/10.1128/mcb.22.16.5879-5886.2002.

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ABSTRACT Using a subtractive cDNA library hybridization approach, we found that receptor interacting protein 2 (RIP2), a tumor necrosis factor receptor 1 (TNFR-1)-associated factor, is a novel early-acting gene that decreases markedly in expression during myogenic differentiation. RIP2 consists of three domains: an amino-terminal kinase domain, an intermediate domain, and a carboxy-terminal caspase activation and recruitment domain (CARD). In some cell types, RIP2 has been shown to be a potent inducer of apoptosis and an activator of NF-κB. To analyze the function of RIP2 during differentiation, we transduced C2C12 myoblasts with retroviral vectors to constitutively produce RIP2 at high levels. When cultured in growth medium, these cells did not show an enhanced rate of proliferation compared to controls. When switched to differentiation medium, however, they continued to proliferate, whereas control cells withdrew from the cell cycle, showed increased expression of differentiation markers such as myogenin, and began to differentiate into multinucleated myotubes. The complete RIP2 protein appeared to be necessary to inhibit myogenic differentiation, since two different deletion mutants lacking either the amino-terminal kinase domain or the carboxy-terminal CARD had no effect. A mutant deficient in kinase activity, however, had effects similar to wild-type RIP2, indicating that phosphorylation was not essential to the function of RIP2. Furthermore, RIP proteins appeared to be important during myogenic differentiation in vivo, as we detected a marked decrease in expression of the RIP2 homolog RIP in several muscle tissues of the dystrophic mdx mouse, a model for continuous muscle degeneration and regeneration. We conclude that RIP proteins can act independently of TNFR-1 stimulation by ligand to modulate downstream signaling pathways, such as activation of NF-κB. These results implicate RIP2 in a previously unrecognized role: a checkpoint for myogenic proliferation and differentiation.

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Sell, Stewart, et Zoran Ilic. « Comparison of survivor scores for differentiation therapy of cancer to those for checkpoint inhibition : Half full or half empty ». Tumor Biology 41, n^o 9 (septembre 2019) : 101042831987374. http://dx.doi.org/10.1177/1010428319873749.

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Differentiation therapy is directed to the self-renewing cancer stem cells, as well as their progeny transit amplifying cells, to force them to mature to terminal differentiation. Differentiation therapy is effective in treatment of neuroblastomas and myeloid leukemias. Checkpoint inhibition therapy removes blocks to cancer reactive T-killer cells and allows them to react to malignant cells and limit the growth of cancer. The percentage of patients with a given cancer that responds to either therapy is less than hoped for, and the duration of response is variable. Multiplying the response rate (percentage of patients responding to therapy) by the duration of response may be used to derive a survival score for patients treated with differentiation therapy or checkpoint inhibition. By this criterion, differentiation therapy gives better survival scores than checkpoint inhibition. Yet, checkpoint inhibition is considered a great success, mostly because it may be applied to many different types of cancer, and differentiation therapy is considered relatively ineffective because it is limited to a few specific cancers. On the other hand, the cost of checkpoint inhibition treatment is 10–20 times more per patient than that of differentiation therapy. Hopefully, future combined treatments and advances in both approaches will increase the effectiveness of these cancer treatments.

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Vining, Kyle H., Anna E. Marneth, Kwasi Adu-Berchie, Christina M. Tringides, Joshua M. Grolman, Yutong Liu, Waihay J. Wong et al. « Mechanical Checkpoint Regulates Monocyte Differentiation in Fibrotic Matrix ». Blood 138, Supplement 1 (5 novembre 2021) : 2539. http://dx.doi.org/10.1182/blood-2021-147297.

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Abstract Myelofibrosis (MF) is a progressive, myeloid malignancy characterized by deposition of collagen and reticulin fibers in the bone marrow (BM). Previous studies have shown that monocytosis is associated with poor prognosis in MF, highlighting a potential pathogenic role for monocytes in MF. Although many studies have addressed the role of cell-intrinsic and soluble extracellular factors in MF development, it is currently unknown if mechanical properties of fibrotic BM contribute to aberrant differentiation of myeloid cells and of monocytes in particular. We first defined the stiffness and viscoelastic properties of healthy and fibrotic BM. Stiffness is defined as the resistance of a matrix to deformation, while viscoelasticity is the rate of dissipation of an applied stress over time. Independent of stiffness, an applied stress relaxes rapidly in a more viscous, liquid-like matrix, whereas in a more elastic, solid-like material, stress relaxes slowly. We next generated a cohort of fibrotic and non-fibrotic mice by transplanting retrovirally transduced JAK2V617F or empty vector (EV) control hematopoietic stem and progenitor cells (HSPCs) into lethally irradiated recipients. Femurs from these mice were harvested seven months post-transplant, as well as from age- and sex-matched healthy primary mice. Nanoindentation was performed to measure BM stiffness and viscoelasticity. Fibrotic BM showed higher stiffness, as well as trending higher elastic, solid-like properties, compared to BM of control mice. We then aimed to study the effect of matrix stiffness and viscoelasticity on monocytes. Human BM-derived monocytes were encapsulated in stiff, viscous or stiff, elastic hydrogels and cultured in the presence of GM-CSF, IL-4, and PGE2 for 3 days, followed by nanoString and flow cytometry analyses. Cells in elastic gels upregulated gene sets associated with co-stimulatory molecules and cytokine receptor signaling, MHC class II antigen presentation, and regulation of extracellular matrix (ECM), compared to cells in viscous gels of the same stiffness. The fraction of dendritic cells (DCs) was significantly upregulated, as indicated by double-positive CD11c+CD1c+ (40.9% viscous vs 69.5% elastic of CD11b+HLA-DR+ cells) and CD80+ cells (20.9% viscous vs 62.7% elastic of CD11b+HLA-DR+ cells), and surface expression of HLA-DR (gMFI 2587 viscous vs 6334 elastic). Consistent with these findings, the fraction of pro-fibrotic SLAMF7+ cells (4.2% viscous vs 17.3% elastic) were also significantly higher in elastic gels. Together, these data suggest that stiff, elastic ECM drives pro-inflammatory polarization and differentiation of monocytes into antigen-presenting cells. Next, we examined the role of the cytoskeleton on human monocyte differentiation. Cortical F-actin was significantly upregulated in cells in stiff, elastic gels compared to viscous gels. Cells were exposed to a highly selective small molecular inhibitor of the γ-isoform of PI3K. Treatment with the PI3Ky inhibitor significantly reduced F-actin staining of cells in elastic gels, upregulated immature monocyte markers, reduced surface expression of HLA-DR, and downregulated the cytokines IL6, IL8, CCL4, which have previously been associated with disease progression in myelofibrosis. In line with the above human ex vivo data, BM isolated from fibrotic mice (described above) showed skewing towards Ly6G-Ly6C+ monocytes (a population enriched for inflammatory monocytes) within the CD11b myeloid compartment compared to control transplanted mice or to non-fibrotic mice that were transplanted with endogenously expressing Jak2V617F cells. Additionally, the percentage of conventional DCs (cDCs) was increased in fibrotic Jak2V617F mice compared to control mice. Importantly, 16 day in vivo treatment with the PI3Ky inhibitor significantly reduced the fraction of Ly6G-Ly6C+ monocytes within the CD11b compartment as well as the fraction of cDCs, compared to vehicle-treated Jak2V617F mice. In summary, fibrotic BM is stiffer and more elastic than normal BM. Our studies show that a stiff, elastic BM environment drives monocytes towards a more pro-inflammatory state which can in part be suppressed by PI3K-γ inhibition. Our results have relevance for human MF by demonstrating that a fibrotic BM niche is not just a consequence of chronic inflammation but is also inflammation-promoting. KHV and AEM contributed equally to this work. Disclosures Pozdnyakova: Scopio Labs: Consultancy. Mullally: Janssen, PharmaEssentia, Constellation and Relay Therapeutics: Consultancy. Wucherpfennig: Novartis: Research Funding; Nextechinvest: Membership on an entity's Board of Directors or advisory committees; Immunitas Therapeutics: Current holder of individual stocks in a privately-held company; TScan Therapeutics: Membership on an entity's Board of Directors or advisory committees; TCR2 Therapeutics: Membership on an entity's Board of Directors or advisory committees; SQZ Biotech: Membership on an entity's Board of Directors or advisory committees. Mooney: Novartis: Patents & Royalties: Licensed IP, Research Funding; Sirenex: Patents & Royalties: Licensed IP; Samyang Corp: Membership on an entity's Board of Directors or advisory committees; IVIVA: Membership on an entity's Board of Directors or advisory committees; Attivare: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Revela: Membership on an entity's Board of Directors or advisory committees; Amend Surgical: Patents & Royalties: Licensed IP; Lyell: Current equity holder in publicly-traded company, Patents & Royalties.

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Puri, Pier Lorenzo, Kunjan Bhakta, Lauren D. Wood, Antonio Costanzo, Jiangyu Zhu et Jean Y. J. Wang. « A myogenic differentiation checkpoint activated by genotoxic stress ». Nature Genetics 32, n^o 4 (4 novembre 2002) : 585–93. http://dx.doi.org/10.1038/ng1023.

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Krauss, Jennifer L., Rong Zeng, Cynthia L. Hickman-Brecks, Justin E. Wilson, Jenny P. Y. Ting et Deborah V. Novack. « NLRP12 provides a critical checkpoint for osteoclast differentiation ». Proceedings of the National Academy of Sciences 112, n^o 33 (3 août 2015) : 10455–60. http://dx.doi.org/10.1073/pnas.1500196112.

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The alternative or noncanonical nuclear factor kappa B (NF-κB) pathway regulates the osteoclast (OC) response to receptor activator of nuclear factor kappa B ligand (RANKL) and thus bone metabolism. Although several lines of evidence support the emerging concept that nucleotide-binding leucine-rich repeat and pyrin domain-containing receptor 12 (NLRP12) impedes alternative NF-κB activation in innate immune cells, a functional role for NLRP12 outside an inflammatory disease model has yet to be reported. Our study demonstrates that NLRP12 has a protective role in bone via suppression of alternative NF-κB–induced osteoclastogenesis and is down-modulated in response to osteoclastogenic stimuli. Here, we show that retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and OC formation. Conversely, genetic ablation of NLRP12 promoted NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro. Using radiation chimeras, we demonstrated these in vitro observations dovetail with our in vivo findings that NLRP12 deficiency leads to enhanced OC numbers accompanied by a significant decline in bone mass under physiological conditions. Consistent with the basal bone phenotype, we also observed an enhanced osteolytic response following RANKL injection over the calvaria of NLRP12-deficient chimeric mice compared with wild-type control mice. Thus, modulation of NLRP12 levels controls alternative NF-κB signaling in OC precursors, altering bone homeostasis and osteolytic responses.

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Roth, Therese M., C. Y. Ason Chiang, Mayu Inaba, Hebao Yuan, Viktoria Salzmann, Caitlin E. Roth et Yukiko M. Yamashita. « Centrosome misorientation mediates slowing of the cell cycle under limited nutrient conditions in Drosophila male germline stem cells ». Molecular Biology of the Cell 23, n^o 8 (15 avril 2012) : 1524–32. http://dx.doi.org/10.1091/mbc.e11-12-0999.

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Drosophila male germline stem cells (GSCs) divide asymmetrically, balancing self-renewal and differentiation. Although asymmetric stem cell division balances between self-renewal and differentiation, it does not dictate how frequently differentiating cells must be produced. In male GSCs, asymmetric GSC division is achieved by stereotyped positioning of the centrosome with respect to the stem cell niche. Recently we showed that the centrosome orientation checkpoint monitors the correct centrosome orientation to ensure an asymmetric outcome of the GSC division. When GSC centrosomes are not correctly oriented with respect to the niche, GSC cell cycle is arrested/delayed until the correct centrosome orientation is reacquired. Here we show that induction of centrosome misorientation upon culture in poor nutrient conditions mediates slowing of GSC cell proliferation via activation of the centrosome orientation checkpoint. Consistently, inactivation of the centrosome orientation checkpoint leads to lack of cell cycle slowdown even under poor nutrient conditions. We propose that centrosome misorientation serves as a mediator that transduces nutrient information into stem cell proliferation, providing a previously unappreciated mechanism of stem cell regulation in response to nutrient conditions.

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Rabadi, Dina, Alia A. Sajani, Randolph J. Noelle et J. Louise Lines. « The role of VISTA in the tumor microenvironment ». Journal of Cancer Metastasis and Treatment 8, n^o 5 (2022) : 24. http://dx.doi.org/10.20517/2394-4722.2022.06.

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V-domain Ig Suppressor of T cell Activation (VISTA) is a negative immune checkpoint that is expressed on multiple immune cell subsets and has been characterized in T cells, macrophages, and myeloid-derived suppressor cells. As the only immune checkpoint expressed on naïve T cells, VISTA contributes to the maintenance of T cell quiescence and tolerance. VISTA also regulates multiple myeloid cell activities such as chemotaxis, differentiation, and migration. In the context of cancer, antagonistic monoclonal antibody targeting of VISTA has been shown to aid anti-tumor immunity. Furthermore, combination therapies that include other immune checkpoints such as PD-1 or CTLA-4 with VISTA blockade may enhance therapeutic efficacy in a variety of cancers. Combination therapy may help overcome adaptive resistance to individual checkpoint therapies, thereby improving patient outcomes and survival. Here, we summarize the role of VISTA in myeloid cells and T cells within the tumor microenvironment. We discuss the proposed counter-receptors for VISTA, VISTA antibodies currently in development, and the potential for combination therapies with checkpoint inhibitors such as PD-1 and CTLA-4.

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Abbadi, Dounia, Ming Yang, Devon M. Chenette, John J. Andrews et Robert J. Schneider. « Muscle development and regeneration controlled by AUF1-mediated stage-specific degradation of fate-determining checkpoint mRNAs ». Proceedings of the National Academy of Sciences 116, n^o 23 (21 mai 2019) : 11285–90. http://dx.doi.org/10.1073/pnas.1901165116.

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AUF1 promotes rapid decay of mRNAs containing 3′ untranslated region (3′UTR) AU-rich elements (AREs). AUF1 depletion in mice accelerates muscle loss and causes limb girdle muscular dystrophy. Here, we demonstrate that the selective, targeted degradation by AUF1 of key muscle stem cell fate-determining checkpoint mRNAs regulates each stage of muscle development and regeneration by reprogramming each myogenic stage. Skeletal muscle stem (satellite) cell explants show that Auf1 transcription is activated with satellite cell activation by stem cell regulatory factor CTCF. AUF1 then targets checkpoint ARE-mRNAs for degradation, progressively reprogramming the transcriptome through each stage of myogenesis. Transition steps in myogenesis, from stem cell proliferation to differentiation to muscle fiber development, are each controlled by fate-determining checkpoint mRNAs, which, surprisingly, were found to be controlled in their expression by AUF1-targeted mRNA decay. Checkpoint mRNAs targeted by AUF1 include Twist1, decay of which promotes myoblast development; CyclinD1, decay of which blocks myoblast proliferation and initiates differentiation; and RGS5, decay of which activates Sonic Hedgehog (SHH) pathway-mediated differentiation of mature myotubes. AUF1 therefore orchestrates muscle stem cell proliferation, self-renewal, myoblast differentiation, and ultimately formation of muscle fibers through targeted, staged mRNA decay.

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Dirlam, Alexandra, Benjamin T. Spike et Kay F. Macleod. « E2f-2 Regulates Caspase-3 Expression and Mitotic Checkpoint Control during End-Stage Erythroid Maturation. » Blood 106, n^o 11 (16 novembre 2005) : 307. http://dx.doi.org/10.1182/blood.v106.11.307.307.

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Abstract E2f-2 is a member of the E2F superfamily of transcription factors that plays multiple roles in regulating cell cycle progression, cell cycle exit and checkpoint control [1]. While over-expression studies have ascribed a role for E2f-2 as a transcriptional activator of cell cycle genes, our loss of function studies performed in vivo have revealed a novel role for E2f-2 in repressing cellular proliferation and mediating differentiation. Our expression analyses demonstrate that E2f-2 is up-regulated in hematopoietic tissues, and is most strongly expressed in differentiating erythroblasts. Furthermore, E2f-2 is the major pRb-associated E2F in hematopoietic tissues, suggesting E2f-2 can function as a co-repressor of cell cycle genes during end-stage differentiation. Compound Rb−/−;E2f2−/− mice were generated to understand how deregulated E2f-2 activity contributes to the erythroid defects in Rb null mice. Loss of E2f-2 restored end-stage erythroid differentiation and enucleation to Rb null erythroblasts and extended survival of Rb null mice. Loss of E2f-2 was sufficient to bypass the mitotic arrest observed in Rb null erythroblasts [2] and was associated with reduced expression of known E2f target genes involved in M phase checkpoint control, such as Aurora B and Survivin. In addition, we observed a significant increase in caspase-3 expression in E2f-2 null erythroblasts and demonstrate, for the first time, direct regulation of caspase-3 expression by E2f-2. Given known roles for caspases in promoting erythroid differentiation and enucleation, we have over-expressed caspase-3 in Rb null erythroblasts and are currently analyzing its effects on cell cycle and maturation. Thus, our work identifies caspase-3 as a key downstream target of E2f-2 during end-stage erythroid differentiation whose expression may alleviate enucleation and mitotic defects in Rb null erythroblasts. Future work aims to understand which E2f-2 target genes ensure mitotic checkpoint control, and the molecular mechanism by which caspase-3 coordinates cell cycle control with erythroid differentiation.

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Andrews, Lauren B., Alec A. K. Nielsen et Christopher A. Voigt. « Cellular checkpoint control using programmable sequential logic ». Science 361, n^o 6408 (20 septembre 2018) : eaap8987. http://dx.doi.org/10.1126/science.aap8987.

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Biological processes that require orderly progression, such as growth and differentiation, proceed via regulatory checkpoints where the cell waits for signals before continuing to the next state. Implementing such control would allow genetic engineers to divide complex tasks into stages. We present genetic circuits that encode sequential logic to instructEscherichia colito proceed through a linear or cyclical sequence of states. These are built with 11 set-reset latches, designed with repressor-based NOR gates, which can connect to each other and sensors. The performance of circuits with up to three latches and four sensors, including a gated D latch, closely match predictions made by using nonlinear dynamics. Checkpoint control is demonstrated by switching cells between multiple circuit states in response to external signals over days.

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Maeda, Yasuo. « Cell-cycle checkpoint for transition from cell division to differentiation ». Development, Growth & ; Differentiation 53, n^o 4 (mai 2011) : 463–81. http://dx.doi.org/10.1111/j.1440-169x.2011.01264.x.

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Gandarillas, Alberto, Rut Molinuevo, Ana Freije et Pilar Alonso-Lecue. « The mitosis-differentiation checkpoint, another guardian of the epidermal genome ». Molecular & ; Cellular Oncology 2, n^o 3 (21 janvier 2015) : e997127. http://dx.doi.org/10.1080/23723556.2014.997127.

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Martinikova, Andra S., Monika Burocziova, Miroslav Stoyanov et Libor Macurek. « Truncated PPM1D Prevents Apoptosis in the Murine Thymus and Promotes Ionizing Radiation-Induced Lymphoma ». Cells 9, n^o 9 (10 septembre 2020) : 2068. http://dx.doi.org/10.3390/cells9092068.

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Genome integrity is protected by the cell-cycle checkpoints that prevent cell proliferation in the presence of DNA damage and allow time for DNA repair. The transient checkpoint arrest together with cellular senescence represent an intrinsic barrier to tumorigenesis. Tumor suppressor p53 is an integral part of the checkpoints and its inactivating mutations promote cancer growth. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of p53. Although its loss impairs recovery from the G2 checkpoint and promotes induction of senescence, amplification of the PPM1D locus or gain-of-function truncating mutations of PPM1D occur in various cancers. Here we used a transgenic mouse model carrying a truncating mutation in exon 6 of PPM1D (Ppm1dT). As with human cell lines, we found that the truncated PPM1D was present at high levels in the mouse thymus. Truncated PPM1D did not affect differentiation of T-cells in the thymus but it impaired their response to ionizing radiation (IR). Thymocytes in Ppm1dT/+ mice did not arrest in the checkpoint and continued to proliferate despite the presence of DNA damage. In addition, we observed a decreased level of apoptosis in the thymi of Ppm1dT/+ mice. Moreover, the frequency of the IR-induced T-cell lymphomas increased in Ppm1dT/+Trp53+/− mice resulting in decreased survival. We conclude that truncated PPM1D partially suppresses the p53 pathway in the mouse thymus and potentiates tumor formation under the condition of a partial loss of p53 function.

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Kondratova, Maria, Emmanuel Barillot, Andrei Zinovyev et Laurence Calzone. « Modelling of Immune Checkpoint Network Explains Synergistic Effects of Combined Immune Checkpoint Inhibitor Therapy and the Impact of Cytokines in Patient Response ». Cancers 12, n^o 12 (2 décembre 2020) : 3600. http://dx.doi.org/10.3390/cancers12123600.

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After the success of the new generation of immune therapies, immune checkpoint receptors have become one important center of attention of molecular oncologists. The initial success and hopes of anti-programmed cell death protein 1 (anti-PD1) and anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) therapies have shown some limitations since a majority of patients have continued to show resistance. Other immune checkpoints have raised some interest and are under investigation, such as T cell immunoglobulin and ITIM (immunoreceptor tyrosine-based inhibition motif) domain (TIGIT), inducible T-cell costimulator (ICOS), and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), which appear as promising targets for immunotherapy. To explore their role and study possible synergetic effects of these different checkpoints, we have built a model of T cell receptor (TCR) regulation including not only PD1 and CTLA4, but also other well studied checkpoints (TIGIT, TIM3, lymphocyte activation gene 3 (LAG3), cluster of differentiation 226 (CD226), ICOS, and tumour necrosis factor receptors (TNFRs)) and simulated different aspects of T cell biology. Our model shows good correspondence with observations from available experimental studies of anti-PD1 and anti-CTLA4 therapies and suggest efficient combinations of immune checkpoint inhibitors (ICI). Among the possible candidates, TIGIT appears to be the most promising drug target in our model. The model predicts that signal transducer and activator of transcription 1 (STAT1)/STAT4-dependent pathways, activated by cytokines such as interleukin 12 (IL12) and interferon gamma (IFNG), could improve the effect of ICI therapy via upregulation of Tbet, suggesting that the effect of the cytokines related to STAT3/STAT1 activity is dependent on the balance between STAT1 and STAT3 downstream signalling.

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Jiang, Yi Wei, et Christopher Minkyu Kang. « Induction of S. cerevisiae Filamentous Differentiation by Slowed DNA Synthesis Involves Mec1, Rad53 and Swe1 Checkpoint Proteins ». Molecular Biology of the Cell 14, n^o 12 (décembre 2003) : 5116–24. http://dx.doi.org/10.1091/mbc.e03-06-0375.

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A key question in eukaryotic differentiation is whether there are common regulators or biochemical events that are required for diverse types of differentiation or whether there is a core mechanism for differentiation. The unicellular model organism Saccharomyces cerevisiae undergoes filamentous differentiation in response to environmental cues. Because conserved cell cycle regulators, the mitotic cyclin-dependent kinase Clb2/Cdc28, and its inhibitor Swe1 were found to be involved in both nitrogen starvation- and short chain alcohol-induced filamentous differentiation, they were identified as components of the core mechanism for filamentous differentiation. We report here that slowed DNA synthesis also induces yeast filamentous differentiation through conserved checkpoint proteins Mec1 and Rad53. Swe1 and Clb2 are also involved in this form of differentiation, and the core status of Swe1/Clb2/Cdc28 in the mechanism of filamentous differentiation has therefore been confirmed. Because the cAMP and filamentous growth mitogen-activated protein kinase pathways that mediate nitrogen starvation-induced filamentous differentiation are not required for slowed DNA synthesis-induced filamentous growth, they can therefore be excluded from the core mechanism. More significantly, slowed DNA synthesis also induces differentiation in mammalian cancer cells, and such stimulus conservation may indicate that the core mechanism for yeast filamentous differentiation is conserved in mammalian differentiation.

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Xiao, Qingyang, André Nobre, Pilar Piñeiro, Miguel-Ángel Berciano-Guerrero, Emilio Alba, Manuel Cobo, Volker Lauschke et Isabel Barragán. « Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response ». Journal of Clinical Medicine 9, n^o 1 (20 janvier 2020) : 286. http://dx.doi.org/10.3390/jcm9010286.

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Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.

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Zha, Zhao, Felicitas Bucher, Anahita Nejatfard, Tianqing Zheng, Hongkai Zhang, Kyungmoo Yea et Richard A. Lerner. « Interferon-γ is a master checkpoint regulator of cytokine-induced differentiation ». Proceedings of the National Academy of Sciences 114, n^o 33 (31 juillet 2017) : E6867—E6874. http://dx.doi.org/10.1073/pnas.1706915114.

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Cytokines are protein mediators that are known to be involved in many biological processes, including cell growth, survival, inflammation, and development. To study their regulation, we generated a library of 209 different cytokines. This was used in a combinatorial format to study the effects of cytokines on each other, with particular reference to the control of differentiation. This study showed that IFN-γ is a master checkpoint regulator for many cytokines. It operates via an autocrine mechanism to elevate STAT1 and induce internalization of gp130, a common component of many heterodimeric cytokine receptors. This targeting of a receptor subunit that is common to all members of an otherwise diverse family solves the problem of how a master regulator can control so many diverse receptors. When one adds an autocrine mechanism, fine control at the level of individual cells is achieved.

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Chann, Anchi S., et Sarah M. Russell. « An integrated transcriptional switch at the β-selection checkpoint determines T cell survival, development and leukaemogenesis ». Biochemical Society Transactions 47, n^o 4 (27 juin 2019) : 1077–89. http://dx.doi.org/10.1042/bst20180414.

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Abstract In T cell development, a pivotal decision-making stage, termed β-selection, integrates a TCRβ checkpoint to coordinate survival, proliferation and differentiation to an αβ T cell. Here, we review how transcriptional regulation coordinates fate determination in early T cell development to enable β-selection. Errors in this transcription control can trigger T cell acute lymphoblastic leukaemia. We describe how the β-selection checkpoint goes awry in leukaemic transformation.

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Derakhshani, Afshin, Zeinab Rostami, Hossein Safarpour, Mahdi Abdoli Shadbad, Niloufar Sadat Nourbakhsh, Antonella Argentiero, Sina Taefehshokr et al. « From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells : Changing the Landscape of Cancer Immunotherapy ». Molecules 26, n^o 8 (14 avril 2021) : 2278. http://dx.doi.org/10.3390/molecules26082278.

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Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

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Wong, Gladys, Juan Carlos Zuniga-Pflucker, Gisele Knowles, Tak Mak et Adolfo Ferrando. « Molecular targets of Notch signaling, HES1 and c-Myc, oppose a PTEN-dependent check on survival, differentiation and proliferation of TCR-beta-selected thymocytes (111.21) ». Journal of Immunology 188, n^o 1_Supplement (1 mai 2012) : 111.21. http://dx.doi.org/10.4049/jimmunol.188.supp.111.21.

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Abstract The developmental progression of immature thymocytes requires cooperative input from several pathways. Notch signals playing an indispensible role at the T cell receptor (TCR)-beta selection checkpoint, by activating the PI3K/Akt pathway, which is required for pT-alpha/TCR-beta (preTCR)-induced survival, differentiation and proliferation of developing alphabeta-lineage thymocytes. However, the molecular players responsible for this interaction between the Notch and PI3K pathways are unknown. Here, we show that Notch induction of Hes1 is necessary to repress the PI3K/Akt pathway inhibitor, PTEN, which in turn facilitates preTCR-induced differentiation. In support of this mechanism, deletion or down-regulation of Pten overcomes the Notch signaling requirement for survival and differentiation during beta-selection. Additionally, c-Myc is a critical target of Notch at this stage, as c-Myc expression overcomes the Notch signaling requirement for proliferation during beta-selection. Collectively, our results point to HES1, via repression of PTEN, and c-Myc as critical mediators of Notch function at the beta-selection checkpoint.

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Srour, Nivine, Guillaume Chemin, Aurélien Tinguely, Mohamad Omar Ashi, Zéliha Oruc, Sophie Péron, Christophe Sirac, Michel Cogné et Laurent Delpy. « A plasma cell differentiation quality control ablates B cell clones with biallelic Ig rearrangements and truncated Ig production ». Journal of Experimental Medicine 213, n^o 1 (14 décembre 2015) : 109–22. http://dx.doi.org/10.1084/jem.20131511.

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Aberrantly rearranged immunoglobulin (Ig) alleles are frequent. They are usually considered sterile and innocuous as a result of nonsense-mediated mRNA decay. However, alternative splicing can yield internally deleted proteins from such nonproductively V(D)J-rearranged loci. We show that nonsense codons from variable (V) Igκ exons promote exon-skipping and synthesis of V domain-less κ light chains (ΔV-κLCs). Unexpectedly, such ΔV-κLCs inhibit plasma cell (PC) differentiation. Accordingly, in wild-type mice, rearrangements encoding ΔV-κLCs are rare in PCs, but frequent in B cells. Likewise, enforcing expression of ΔV-κLCs impaired PC differentiation and antibody responses without disturbing germinal center reactions. In addition, PCs expressing ΔV-κLCs synthesize low levels of Ig and are mostly found among short-lived plasmablasts. ΔV-κLCs have intrinsic toxic effects in PCs unrelated to Ig assembly, but mediated by ER stress–associated apoptosis, making PCs producing ΔV-κLCs highly sensitive to proteasome inhibitors. Altogether, these findings demonstrate a quality control checkpoint blunting terminal PC differentiation by eliminating those cells expressing nonfunctionally rearranged Igκ alleles. This truncated Ig exclusion (TIE) checkpoint ablates PC clones with ΔV-κLCs production and exacerbated ER stress response. The TIE checkpoint thus mediates selection of long-lived PCs with limited ER stress supporting high Ig secretion, but with a cost in terms of antigen-independent narrowing of the repertoire.

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Qin, Yuling, Meiqin Li, Qiumei Lin, Xiaolan Pan, Yihua Liang, Zhaodong Huang, Zhimin Liu, Lingsha Huang et Min Fang. « Colorectal Cancer Cell Differentiation Trajectory Predicts Patient Immunotherapy Response and Prognosis ». Cancer Control 29 (janvier 2022) : 107327482211213. http://dx.doi.org/10.1177/10732748221121382.

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Objectives This study aimed to investigate the differentiation state and clinical significance of colorectal cancer cells, as well as to predict the immune response and prognosis of patients based on differentiation-related genes of colorectal cancer. Introduction Colorectal cancer cells exhibit different differentiation states under the influence of the tumor microenvironment, which determines the cell fates. Methods We combined single-cell sequencing (scRNA-seq) data from The Cancer Genome Atlas source with extensive transcriptome data from the Gene Expression Omnibus database. We obtained colorectal cancer differentiation-related genes using cell trajectory analysis and developed a colorectal cancer differentiation-related gene based molecular typing and prognostic model to predict the immune response and prognosis of patients with colorectal cancer. Results We identified 5 distinct cell differentiation subsets and 620 colorectal cancer differentiation-related genes. Colorectal cancer differentiation-related genes were significantly associated with metabolism, angiogenesis, and immunity. We separated patients into 3 subtypes based on colorectal cancer differentiation-related gene expression in the tumor and found differences among the different subtypes in immune infiltration status, immune checkpoint gene expression, clinicopathological features, and overall survival. Immunotherapeutic interventions involving a highly expressed immune checkpoint blockade may be selectively effective in the corresponding cancer subtypes. We built a risk score prediction model (5-year AUC: .729) consisting of the 4 most important predictors of survival (TIMP1, MMP1, LGALS4, and ITLN1). Finally, we generated and validated a nomogram consisting of the risk score and clinicopathological variables. Conclusion This study highlights the significance of genes involved in cell differentiation for clinical prognosis and immunotherapy in patients and provides prospective therapeutic targets for colorectal cancer.

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Wong, Gladys W., Gisele C. Knowles, Tak W. Mak, Adolfo A. Ferrando et Juan Carlos Zúñiga-Pflücker. « HES1 opposes a PTEN-dependent check on survival, differentiation, and proliferation of TCRβ-selected mouse thymocytes ». Blood 120, n^o 7 (16 août 2012) : 1439–48. http://dx.doi.org/10.1182/blood-2011-12-395319.

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Abstract The developmental progression of immature thymocytes requires cooperative input from several pathways, with Notch signals playing an indispensable role at the T-cell receptor (TCR)–β selection checkpoint. Notch signals affect the activation of the PI3K/Akt pathway, which is required for pTα/TCRβ (pre-TCR)–induced survival, differentiation, and proliferation of developing αβ-lineage thymocytes. However, the molecular players responsible for the interaction between the Notch and PI3K pathways at this critical developmental stage are unknown. Here, we show that Notch induction of Hes1 is necessary to repress the PI3K/Akt pathway inhibitor, PTEN (phosphatase and tensin homolog), which in turn facilitates pre-TCR–induced differentiation. In support of this mechanism, deletion or down-regulation of Pten overcomes the Notch signaling requirement for survival and differentiation during β-selection. In addition, c-Myc is a critical target of Notch at this stage, as c-Myc expression overcomes the Notch signaling requirement for proliferation during β-selection. Collectively, our results point to HES1, via repression of PTEN, and c-Myc as critical mediators of Notch function at the β-selection checkpoint.

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Ullah, Z., C. de Renty et M. L. DePamphilis. « Checkpoint Kinase 1 Prevents Cell Cycle Exit Linked to Terminal Cell Differentiation ». Molecular and Cellular Biology 31, n^o 19 (26 juillet 2011) : 4129–43. http://dx.doi.org/10.1128/mcb.05723-11.

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Gandarillas, Alberto. « The mysterious human epidermal cell cycle, or an oncogene-induced differentiation checkpoint ». Cell Cycle 11, n^o 24 (15 décembre 2012) : 4507–16. http://dx.doi.org/10.4161/cc.22529.

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Yang, Fan, Yan Zhao, Xiaohan Huang, Jin Zhang et Ting Zhang. « A Cell Differentiation Trajectory-Related Signature for Predicting the Prognosis of Lung Adenocarcinoma ». Genetics Research 2022 (16 août 2022) : 1–11. http://dx.doi.org/10.1155/2022/3483498.

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Objective. To screen the cell differentiation trajectory-related genes and build a cell differentiation trajectory-related signature for predicting the prognosis of lung adenocarcinoma (LUAD). Methods. LUAD single cell mRNA expression profile, TCGA-LUAD transcriptome data were obtained from GEO and TCGA databases. Single-cell RNA-seq data were used for cell clustering and pseudotime analysis after dimensionality reduction analysis, and the cell differentiation trajectory-related genes were acquired after differential expression analysis conducted between the main branches. Then, the consensus clustering analysis was carried out on TCGA-LUAD samples, and the GSEA analysis was performed, then the differences on the expression levels of immune checkpoint genes and immunotherapy response were compared among clusters. The prognostic model was constructed, and the GSE42127 dataset was used to validate. A nomogram evaluation model was used to predict prognosis. Results. Two subsets with distinct differentiation states were found after cell differentiation trajectory analysis. TCGA-LUAD samples were divided into two cell differentiation trajectory-related gene-based clusters, GSEA found that cluster 1 was significantly related to 20 pathways, cluster 2 was significantly enriched in three pathways, and it was also shown that clusters could better predict immune checkpoint gene expression and immunotherapy response. A six cell differentiation-related genes-based prognostic signature was constructed, and the patients in the high-risk group had poorer prognosis than those in the low-risk group. Moreover, a nomogram was constructed based on the prognostic signature and clinicopathological features, and this nomogram had strong predictive performance and high accuracy. Conclusion. The cell differentiation-related signature and the prognostic nomogram could accurately predict survival.

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Hirose, S., Y. Inazu, S. Chae et Y. Maeda. « Suppression of the growth/differentiation transition in Dictyostelium development by transient expression of a novel gene, dia1 ». Development 127, n^o 15 (1 août 2000) : 3263–70. http://dx.doi.org/10.1242/dev.127.15.3263.

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In Dictyostelium discoideum Ax-2 cells, a specific checkpoint (PS point) from which cells enter the differentiation phase in response to starvation has been specified in the cell cycle. Using the differential display method, we isolated a novel gene, dia1 (differentiation-associated gene 1), that is specifically expressed in cells differentiating from the PS point. The dia1 mRNA has an open reading frame of 1,368 bp and is deduced to code for a 48.6 kDa protein (DIA1). The DIA1 protein is highly serine-rich and the serine residues are predominantly located in the C-terminal region. After the PSORT II search, the protein is predicted to be GPI-anchored at the plasma membrane. Unexpectedly, dia1 overexpression rather impaired the progression of differentiation, possibly coupled with the reduced expression of early genes such as cAMP receptor1 (car1). The inhibitory effect of dia1 expression on early differentiation was almost completely nullified by externally applied cAMP pulses. In contrast to dia1 overexpression, antisense RNA-mediated dia1 inactivation was found to enhance the initial step of cell differentiation, as exemplified by precocious expression of car1 and other early genes. We discuss the unique structure and function of DIA1 in relation to the cooperative development of cells during the establishment of multicellular organization.

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Sarkar, Sukumar, Bijan K. Dey et Anindya Dutta. « MiR-322/424 and -503 Are Induced during Muscle Differentiation and Promote Cell Cycle Quiescence and Differentiation by Down-Regulation of Cdc25A ». Molecular Biology of the Cell 21, n^o 13 (juillet 2010) : 2138–49. http://dx.doi.org/10.1091/mbc.e10-01-0062.

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Induction of a G1 phase cell cycle arrest, caused primarily by the inhibition of cyclin-dependent-kinase 2 (cdk2), is a critical step in the differentiation of myoblasts into myotubes. Here, we report that two microRNAs, miR-322/424 and miR-503, are induced and promote cdk2 inhibition during myogenesis. These microRNAs down-regulate Cdc25A, the phosphatase responsible for removing inhibitory phosphorylation of cdk2, both in myoblasts differentiating into myotubes and in nonmuscle cells. Cdc25A is down-regulated during muscle differentiation by multiple pathways: action of these two microRNAs, proteasomal degradation of Cdc25A protein and transcriptional repression. Overexpression of Cdc25A or of cdk2 with mutations on T14 and Y15 (cdk2-AF), so that it cannot be inhibited by phosphorylation, decreases differentiation and differentiation-induced cell cycle quiescence. Introduction of miR-322/424 and miR-503 in heterologous cancer cells induces G1 arrest, which is also attenuated by overexpression of the cdk2-AF mutant. Until now Cdc25A and the inhibitory phosphorylation on T14 and Y15 of cdk2 have only been implicated in the intra-S phase checkpoint pathway after DNA damage. Our results reveal an unexpected role of Cdc25A down-regulation and the inhibitory phosphorylation of cdk2 T14 and Y15 in cell cycle quiescence during muscle differentiation and implicate two muscle differentiation-induced microRNAs in the process.

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Isoda, Takeshi, Masatoshi Takagi, Jinhua Piao, Shun Nakagama, Masaki Sato, Kyoko Masuda, Tomokatsu Ikawa et al. « T-Cell Development Failure At β-Selection Checkpoint and TCRα/δ Locus Break Formation Associated with Chromosome 14 Translocation in Ataxia-Telangiectagia Mutated Deficient Mice ». Blood 118, n^o 21 (18 novembre 2011) : 184. http://dx.doi.org/10.1182/blood.v118.21.184.184.

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Abstract Abstract 184FN2 Ataxia Telangiectagia (AT) is an autosomal recessive immunodeficiency, caused by mutation of ataxia telangiectagia mutated gene (ATM). ATM plays a crucial role for responding to DNA damages by extrinsic and intrinsic factors, and is a master regulator for maintaining DNA integrity. VDJ recombination and class switch recombination during lymphocyte maturation are the steps of intrinsic DNA damage response where ATM stabilizes DNA ends during recombination. ATM deficiency (ATM−/−) is known to predispose to T-cell lymphopenia and T-lineage lymphoma development. ATM−/− mouse has been shown to have a failure of T-cell development at the stage from double positive (DP) to single positive (SP) differentiation, which is due to a failure of T-cell receptor a (TCRa) recombination. Thymic lymphomas in ATM−/− mice have recently been shown to have a chromosome 14 translocation involving TCRd locus, suggesting that the first event for translocation arises during TCRd locus recombination at double negative (DN) stage. However, phenotypic features of T-cell development at DN phase and the timing of chromosome 14 translocation formation in ATM−/− are not fully elucidated. Here we demonstrate that T cells of ATM−/− mice show a failure at the transition from DN3a to DN3b at b and gd-selection checkpoints due to multiple TCR recombination failure in-vivo. Consistent with in-vivo developmental profiles of ATM−/− mice thymocytes, long term hematopoietic stem cells (LTR-HSCs) of ATM−/− mice cultured with OP9-DLL1 show a delay at b-selection checkpoint in chronological order. In this culture system, failures in gd-T-cell development are also observed in ATM−/− LTR-HSCs. Involvement of thymic stromas in the failure of this transition was ruled out by bone-marrow transplantation (BMT) of ATM−/− donor to WT recipient mice, where thymocytes reconstitution showed the same transition failure at b-selection checkpoint. Thymocytes in RAG2−/− mice are arrested at DN3 stage by a failure of cleavage of TCR genes, but the arrested thymocytes are known to progress to DP phase by anti-CD3e antibody stimulation. This experiment enables to analyze pre-TCR dependent differentiation signal machinery. Then anti-CD3e antibody was injected into RAG2−/−ATM−/− mouse and DN3 cells were shown to be led to DP phase, indicating that ATM itself is not involved in the differentiation program during DN to DP phase. These results suggested loss of ATM attenuates T cell differentiation at DN3a to DN3b transition due to inefficient TCRg, d and b locus recombination. Thus differentiation failure from DN3a to DN3b in ATM deficiency is presumably the primary cause of T cell lymphopenia at the stage prior to positive-selection. We next investigated when of the differentiation stages chromosome 14 translocation involving TCRa/d locus monitored. When the LTR-HSCs is cultured on the OP9-DLL1 cells with high-dose cytokine including 10 ng/ml of Flt3-L, IL-7 and SCF, differentiation of LTR-HSCs to T cells halt at DN2-3a phase before b-selection. Then, by reducing the Flt3-L and IL7 to 5 ng/ml and 1 ng/ml, respectively, the differentiation arrest is released and Tcell differentiation progresses from DN3a to DN3b. No detectable chromosome break at TCRad locus was observed at DN2-3a in wild type, while 5% of ATM−/− cells carried TCRad break, associated with chromosome 14 translocation in approximately 0.8 % of DN2-3a cells. After progression to DN3b-4 phase, TCRad locus break was still observed in AT cells at the frequency of 1%, and chromosome 14 translocations involving TCRad locus was observed in 12% of ATM−/− cells, which was in contrast to none in wild type cell. Mono- or bi-allelic TCRa/d breaks, chromosome 14 dicentric, and t (12:14) were also observed in minor population of ATM−/− cells. These results suggest that critical point for generation of chromosome 14 translocations involving TCRa/d locus lies at DN2-3a to 3b stages corresponding during b and gd selection checkpoint in ATM deficient thymocytes. Our findings revealed that developmental failure of T-cells in AT arises during b and gd–selection checkpoint, which leads to the breaks of TCRa/d locus and subsequent chromosome 14 translocation formation. Thus we propose T-lymphopenia and predisposition to T cell leukemia/lymphoma are tightly connected in ATM deficient condition. Disclosures: No relevant conflicts of interest to declare.

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Yu, Jin. « Efficient fidelity control by stepwise nucleotide selection in polymerase elongation Abstract : Polymerases select nucleotides ». Computational and Mathematical Biophysics 2, n^o 1 (1 janvier 2014) : 141–60. http://dx.doi.org/10.2478/mlbmb-2014-0010.

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Abstract Polymerases select nucleotides according to a template before incorporating them for chemical synthesis during gene replication or transcription. Efficient selection to achieve sufficiently high fidelity and speed is essential for polymerase function. Due to multiple kinetic steps detected in a polymerase elongation cycle, there exist multiple selection checkpoints to allow different strategies of fidelity control. In our current work, we examined step-by-step selections in an elongation cycle that have conformational transition rates tuned one at a time, with a controlled differentiation free energy between the right and wrong nucleotides at each checkpoint. The elongation is sustained at non-equilibrium steady state with constant free energy input and heat dissipation. It is found that a selection checkpoint in the later stage of a reaction path has less capability for error reduction. Hence, early selection is essential to achieve an efficient fidelity control. In particular, for an intermediate state, the selection through the forward transition inhibition has the same capacity for error reduction as the selection through the backward rejection. As with respect to the elongation speed, an initial screening is indispensible for maintaining high speed, as the wrong nucleotides can be removed quickly and replaced by the right ones at the entry. Overall, the elongation error rate can be repeatedly reduced through multiple selection checkpoints. This study provides a theoretical framework to guide more detailed structural dynamics studies, and to support rational redesign of related enzymes and devices.

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Ansa-Addo, Ephraim A., Huai-Cheng Huang, Brian Riesenberg, Supinya Iamsawat, Davis Borucki, Michelle H. Nelson, Jin Hyun Nam et al. « RNA binding protein PCBP1 is an intracellular immune checkpoint for shaping T cell responses in cancer immunity ». Science Advances 6, n^o 22 (mai 2020) : eaaz3865. http://dx.doi.org/10.1126/sciadv.aaz3865.

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Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Here, we identify the RNA binding protein, poly(C)-binding protein 1 (PCBP1) as an intracellular immune checkpoint that is up-regulated in activated T cells to prevent conversion of effector T (Teff) cells into regulatory T (Treg) cells, by restricting the expression of Teff cell–intrinsic Treg commitment programs. This was critical for stabilizing Teff cell functions and subverting immune-suppressive signals. T cell–specific deletion of Pcbp1 favored Treg cell differentiation, enlisted multiple inhibitory immune checkpoint molecules including PD-1, TIGIT, and VISTA on tumor-infiltrating lymphocytes, and blunted antitumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular immune checkpoint for maintaining Teff cell functions in cancer immunity.

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Shinnick, Kathryn M., Kelly A. Barry, Elizabeth A. Eklund et Thomas J. McGarry. « Geminin Regulates Hematopoietic Stem Cell Proliferation and Differentiation. » Blood 114, n^o 22 (20 novembre 2009) : 1478. http://dx.doi.org/10.1182/blood.v114.22.1478.1478.

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Abstract Abstract 1478 Poster Board I-501 Hematopoietic stem cells supply the circulation with mature blood cells throughout life. Progenitor cell division and differentiation must be carefully balanced in order to supply the proper numbers and proportions of mature cells. The mechanisms that control the choice between continued cell division and terminal differentiation are incompletely understood. The unstable regulatory protein Geminin is thought to maintain cells in an undifferentiated state while they proliferate. Geminin is a bi-functional protein. It limits the extent of DNA replication to one round per cell cycle by binding and inhibiting the essential replication factor Cdt1. Loss of Geminin leads to replication abnormalities that activate the DNA replication checkpoint and the Fanconi Anemia (FA) pathway. Geminin also influences patterns of cell differentiation by interacting with Homeobox (Hox) transcription factors and chromatin remodeling proteins. To examine how Geminin affects the proliferation and differentiation of hematopoietic stem cells, we created a mouse strain in which Geminin is deleted from the proliferating cells of the bone marrow. Geminin deletion has profound effects on all three hematopoietic lineages. The production of mature erythrocytes and leukocytes is drastically reduced and the animals become anemic and neutropenic. In contrast, the population of megakaryocytes is dramatically expanded and the animals develop thrombocytosis. Interestingly, the number of c-Kit+ Sca1+ Lin- (KSL) stem cells is maintained, at least in the short term. Myeloid colony forming cells are also preserved, but the colonies that grow are smaller. We conclude that Geminin deletion causes a maturation arrest in some lineages and directs cells down some differentiation pathways at the expense of others. We are now testing how Geminin loss affects cell cycle checkpoint pathways, whether Geminin regulates hematopoietic transcription factors, and whether Geminin deficient cells give rise to leukemias or lymphomas. Disclosures: No relevant conflicts of interest to declare.

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OConnor, Roddy, Lili Guo, Saba Ghassemi, Nathaniel Snyder, Andrew Worth, Liwei Weng, Shaun OBrien et al. « Hypoxia-induced reactive oxygen species contribute to immune checkpoint molecule expression in T cells undergoing rapid clonal proliferation ». Journal of Immunology 200, n^o 1_Supplement (1 mai 2018) : 108.18. http://dx.doi.org/10.4049/jimmunol.200.supp.108.18.

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Abstract In response to antigen and costimulation, T cells undergo a series of metabolic transitions supporting clonal expansion and differentiation. We recently showed how CD28 and 4-1BB intracellular co-stimulatory domains induce glycolytic vs oxidative metabolic programs, respectively, in the context of a chimeric antigen receptor. Understanding how endogenous co-stimulatory pathways, in particular CD28, supports differentiation and memory cell development despite encountering hostile environments characterized by varying oxygen tension and metabolic checkpoints is of clear importance to cellular immunotherapy. Immune checkpoint molecule (ICM) expression is associated with T cell exhaustion characterized by reduced proliferative capacity and diminished effector function. While studying the role of LCFAO in primary human T cell differentiation, we uncovered that the CPT1a inhibitor, etomoxir (ETO), induces expression of the PD-1, Tim-3, and Lag-3 ICMs. This is mediated by non-specific effects on oxidative metabolism, culminating in reactive oxygen species (ROS) production. The induction of ICM expression by ETO is calcineurin-dependent and reversed by the antioxidant N-acetylcysteine (NAC). We show that Tim-3 is upregulated by T cells in highly hypoxic xenograft tumors independent of TCR signaling. Transition of highly activated T cell cultures from normoxia (21% O2) to hypoxia (1% O2) induces Tim-3, which is reversed by NAC. These results suggest that ICMs, especially Tim-3, are part of a natural regulatory system that responds to oxidative stress and tempers T cell activation and associated metabolism to minimize oxidative damage to T cell clones expanding following antigen receptor activation.

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Xu, Jin, Xi Chen, Yinyu Chen, Qiushuang Wang, Yingliang Jin et Huashuo Zhao. « Cell Differentiation Trajectory Predicts Prognosis and Immunotherapeutic Response in Clear Cell Renal Cell Carcinoma ». Genetics Research 2022 (29 novembre 2022) : 1–19. http://dx.doi.org/10.1155/2022/8422339.

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Clear cell renal cell carcinoma (ccRCC) is the main type of malignancy in kidney related to glucose metabolism. Primary single cell culture and single cell sequencing are novel research technologies. In this study, we explored the differentiation status of ccRCC cells and its significance in prognosis and immunotherapeutic response through bioinformatics. We characterized distinct differentiation states and differentiation-related genes (DRGs) in ccRCC cells through single cell RNA sequencing (scRNA-seq) analysis. Combined with bulk RNA-seq data, we classified patients into two clusters and found that this classification was closely correlated with patient prognosis and immunotherapeutic responses. Based on machine learning, we identified a prognostic risk model composed of 14 DRGs, including BTG2, CDKN1A, COL6A1, CPM, CYB5D2, FOSB, ID2, ISG15, PLCG2, SECISBP2, SOCS3, TES, ZBTB16, and ZNF704, to predict the survival rate of patients and then constructed a nomogram model integrating clinicopathological characteristics and risk score for clinical practice. In the study of immune checkpoints, we found that patients in the high-risk group had a disposition to get worse prognosis and better effects of immune checkpoint blocking therapies. Finally, we found the expression level of model DRGs was associated with a tumor-immune microenvironment (TIME) pattern and the response of 83 compounds or inhibitors was significantly different in the two risk groups. In a word, our study highlights the potential contribution of cell differentiation in prognosis judgment and immunotherapy response and offers promising therapeutic options for ccRCC patients.

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Devarajan, Priyadharshini, Allen M. Vong, Bianca Bautista, Catherine H. Castonguay et Susan L. Swain. « Antigen Presenting Cells as Drivers of Specialized Immune Responses ». Journal of Immunology 196, n^o 1_Supplement (1 mai 2016) : 133.14. http://dx.doi.org/10.4049/jimmunol.196.supp.133.14.

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Abstract We have defined the “Memory Checkpoint” as the period when CD4 effector T cells (TEFF) require cognate antigen (Ag) recognition for further differentiation into CD4 memory T cells. Using an influenza A virus (IAV) infection model, we find that generation of CD4 cytotoxic T cells (ThCTL) from TEFF requires MHC Class-II restricted Ag at this checkpoint, 5–7 days after initial infection. Ag recognition at this checkpoint also determines CD4 follicular helper T cell (TFH) generation in our model. We have used transgenic mouse models in which Ag presentation is restricted to specific antigen presenting cells (APC), bone marrow chimeras and addition of various APC subsets at the memory checkpoint to study which APC drive TEFF to TFH vs. ThCTL. Our studies indicate that distinct APC, during this checkpoint, promote different fates resulting in generation of distinct effector subsets. While, as expected, B cell APC are necessary for TFH responses, the APC subset(s) that promote ThCTL generation are not yet clear. Our data indicate that a specialized hematopoietic subset of CD11c+ APC, that are preferentially localized in the infected tissue, is required at this checkpoint, to support ThCTL generation. Once we identify the APC subset(s) needed, we plan to target Ag to particular APC at the checkpoint, to uniquely promote distinct functional subsets and evaluate their function. We suggest this may allow us to tailor the quality of the effector response to better protect against distinct pathogens.

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Dong, Juan, Cassandra Gilmore, Hieu Ta, Keman Zhang, Sarah Stone et Li Wang. « 501 VISTA regulates the differentiation and suppressive function of myeloid-derived suppressor cells ». Journal for ImmunoTherapy of Cancer 8, Suppl 3 (novembre 2020) : A536. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0501.

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BackgroundV-domain immunoglobulin suppressor of T cell activation (VISTA) is a B7 family inhibitory immune checkpoint protein and is highly expressed on myeloid cells and T cells.1 VISTA acts as both an inhibitory ligand when expressed on antigen-presenting cells and a receptor when expressed on T cells. Our recent study has shown that VISTA is a myeloid cell-specific immune checkpoint and that blocking VISTA can reprogram suppressive myeloid cells and promote a T cell-stimulatory tumor microenvironment.2 In this study, we further demonstrate that VISTA blockade directly alters the differentiation and the suppressive function of myeloid-derived suppressor cells (MDSC).MethodsFlow cytometry was performed to examine VISTA expression on MDSCs in multiple murine tumor models including the B16BL6 melanoma model, MC38 colon cancer model, and the KPC pancreatic cancer models. To examine the role of VISTA in controlling the differentiation and suppressive function of MDSCs, we cultured wild type (WT) and VISTA.KO bone marrow progenitor cells with GM-CSF and IL-6 to induce BM -derived MDSCs.ResultsOur preliminary results show that VISTA is highly expressed on M-MDSCs in B16BL6, MC38 and KPC tumors. In BM-derived MDSCs, VISTA deletion significantly altered the signaling pathways and the differentiation of MDSCs. Multiple inflammatory signaling pathways were downregulated in VISTA KO MDSCs, resulting in decreased production of cytokines such as IL1 and chemokines such as CCL2/4/9, as well as significantly impaired their ability to suppress the activation of CD8+ T cells. The loss of suppressive function in VISTA KO MDSCs is correlated with significantly reduced expression of iNOS. To validate the results from BM-MDSCs, we sorted CD11b+CD11c-Ly6C+Ly6G- M-MDSCs and CD11b+CD11c-Ly6G+ G-MDSCs from B16BL6 tumor tissues and tested the ability of a VISTA-blocking mAb to reverse the suppressive effects of tumor-derived MDSCs. Our results show that blocking VISTA impaired the suppressive function of tumor-derived M-MDSC but not G-MDSCs.ConclusionsTaken together, these results demonstrate a crucial role of VISTA in regulating the differentiation and function of MDSCs, and that blocking VISTA abolishes MDSC-mediated T cell suppression, thereby boosting.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019-2142).ReferencesXu W, Hire T, Malarkannan, S. et al. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 2018;15:438–446.Xu W, Dong J, Zheng Y, et al. Immune-checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell-mediated inflammation and immunosuppression. Cancer Immunol Res 2019;7:1497–510.

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Schetters, Sjoerd T. T., Ernesto Rodriguez, Laura J. W. Kruijssen, Matheus H. W. Crommentuijn, Louis Boon, Jan Van den Bossche, Joke M. M. Den Haan et Yvette Van Kooyk. « Monocyte-derived APCs are central to the response of PD1 checkpoint blockade and provide a therapeutic target for combination therapy ». Journal for ImmunoTherapy of Cancer 8, n^o 2 (juillet 2020) : e000588. http://dx.doi.org/10.1136/jitc-2020-000588.

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BackgroundPD1 immune checkpoint blockade (αPD1 ICB) has shown unparalleled success in treating many types of cancer. However, response to treatment does not always lead to tumor rejection. While αPD1 ICB relies on cytotoxic CD8+ T cells, antigen-presenting cells (APCs) at the tumor site are also needed for costimulation of tumor-infiltrating lymphocytes (TILs). It is still unclear how these APCs develop and function before and during αPD1 ICB or how they are associated with tumor rejection.MethodsHere, we used B16 mouse melanoma and MC38 colorectal carcinoma tumor models, which show differential responses to αPD1 ICB. The immune composition of ICB insensitive B16 and sensitive MC38 were extensively investigated using multi-parameter flow cytometry and unsupervised clustering and trajectory analyses. We additionally analyzed existing single cell RNA sequencing data of the myeloid compartment of patients with melanoma undergoing αPD1 ICB. Lastly, we investigated the effect of CD40 agonistic antibody on the tumor-infiltrating monocyte-derived cells during αPD1 ICB.ResultsWe show that monocyte-derived dendritic cells (moDCs) express high levels of costimulatory molecules and are correlated with effector TILs in the tumor microenvironment (TME) after αPD1 ICB only in responding mouse tumor models. Tumor-resident moDCs showed distinct differentiation from monocytes in both mouse and human tumors. We further confirmed significant enrichment of tumor-resident differentiated moDCs in patients with melanoma responding to αPD1 ICB therapy compared with non-responding patients. Moreover, moDCs could be targeted by agonistic anti-CD40 antibody, supporting moDC differentiation, effector T-cell expansion and anti-tumor immunity.ConclusionThe combined analysis of myeloid and lymphoid populations in the TME during successful and non-successful PD1 ICB led to the discovery of monocyte-to-DC differentiation linked to expanding T-cell populations. This differentiation was found in patients during ICB, which was significantly higher during successful ICB. The finding of tumor-infiltrating monocytes and differentiating moDCs as druggable target for rational combination therapy opens new avenues of anti-tumor therapy design.

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Renga, Giorgia, Marina M. Bellet, Marilena Pariano, Marco Gargaro, Claudia Stincardini, Fiorella D’Onofrio, Paolo Mosci et al. « Thymosin α1 protects from CTLA-4 intestinal immunopathology ». Life Science Alliance 3, n^o 10 (14 août 2020) : e202000662. http://dx.doi.org/10.26508/lsa.202000662.

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The advent of immune checkpoint inhibitors has represented a major boost in cancer therapy, but safety concerns are increasingly being recognized. Indeed, although beneficial at the tumor site, unlocking a safeguard mechanism of the immune response may trigger autoimmune-like effects at the periphery, thus making the safety of immune checkpoint inhibitors a research priority. Herein, we demonstrate that thymosin α1 (Tα1), an endogenous peptide with immunomodulatory activities, can protect mice from intestinal toxicity in a murine model of immune checkpoint inhibitor–induced colitis. Specifically, Tα1 efficiently prevented immune adverse pathology in the gut by promoting the indoleamine 2,3-dioxygenase (IDO) 1–dependent tolerogenic immune pathway. Notably, Tα1 did not induce IDO1 in the tumor microenvironment, but rather modulated the infiltration of T-cell subsets by inverting the ratio between CD8+ and Treg cells, an effect that may depend on Tα1 ability to regulate the differentiation and chemokine expression profile of DCs. Thus, through distinct mechanisms that are contingent upon the context, Tα1 represents a plausible candidate to improve the safety/efficacy profile of immune checkpoint inhibitors.

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Zhou, Liye, Zexian Zeng, Ann Marie Egloff, Fan Zhang, Fei Guo, Katie M. Campbell, Peter Du et al. « Checkpoint blockade-induced CD8+ T cell differentiation in head and neck cancer responders ». Journal for ImmunoTherapy of Cancer 10, n^o 1 (janvier 2022) : e004034. http://dx.doi.org/10.1136/jitc-2021-004034.

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BackgroundImmune checkpoint blockade (ICB) response in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is limited to 15%–20% of patients and underpinnings of resistance remain undefined.MethodsStarting with an anti-PD1 sensitive murine HNSCC cell line, we generated an isogenic anti-PD1 resistant model. Mass cytometry was used to delineate tumor microenvironments of both sensitive parental murine oral carcinoma (MOC1) and resistant MOC1esc1 tumors. To examine heterogeneity and clonal dynamics of tumor infiltrating lymphocytes (TILs), we applied paired single-cell RNA and TCR sequencing in three HNSCC models.ResultsAnti-PD1 resistant MOC1esc1 line displayed a conserved cell intrinsic immune evasion signature. Immunoprofiling showed distinct baseline tumor microenvironments of MOC1 and MOC1esc1, as well as the remodeling of immune compartments on ICB in MOC1esc1 tumors. Single cell sequencing analysis identified several CD8 +TIL subsets including Tcf7 +Pd1− (naïve/memory-like), Tcf7 +Pd1+ (progenitor), and Tcf7-Pd1+ (differentiated effector). Mapping TCR shared fractions identified that successful anti-PD1 or anti-CTLA4 therapy-induced higher post-treatment T cell lineage transitions.ConclusionsThese data highlight critical aspects of CD8 +TIL heterogeneity and differentiation and suggest facilitation of CD8 +TIL differentiation as a strategy to improve HNSCC ICB response.

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Taghon, Tom, Inge Van de Walle, Greet De Smet, Magda De Smedt, Georges Leclercq, Bart Vandekerckhove et Jean Plum. « Notch signaling is required for proliferation but not for differentiation at a well-defined β-selection checkpoint during human T-cell development ». Blood 113, n^o 14 (2 avril 2009) : 3254–63. http://dx.doi.org/10.1182/blood-2008-07-168906.

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Abstract Notch signaling is absolutely required for β-selection during mouse T-cell development, both for differentiation and proliferation. In this report, we investigated whether Notch has an equally important role during human T-cell development. We show that human CD34+ thymocytes can differentiate into CD4+CD8β+ double positive (DP) thymocytes in the absence of Notch signaling. While these DP cells phenotypically resemble human β-selected cells, they lack a T-cell receptor (TCR)–β chain. Therefore, we characterized the β-selection checkpoint in human T-cell development, using CD28 as a differential marker at the immature single positive CD4+CD3−CD8α− stage. Through intracellular TCR-β staining and gene expression analysis, we show that CD4+CD3−CD8α−CD28+ thymocytes have passed the β-selection checkpoint, in contrast to CD4+CD3−CD8α−CD28− cells. These CD4+CD3−CD8α−CD28+ thymocytes can efficiently differentiate into CD3+TCRαβ+ human T cells in the absence of Notch signaling. Importantly, preselection CD4+CD3−CD8α−CD28− thymocytes can also differentiate into CD3+TCRαβ+ human T cells without Notch activation when provided with a rearranged TCR-β chain. Proliferation of human thymocytes, however, is clearly Notch-dependent. Thus, we have characterized the β-selection checkpoint during human T-cell development and show that human thymocytes require Notch signaling for proliferation but not for differentiation at this stage of development.

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de Joode, Karlijn, Sharon Veenbergen, Claudia Kransse, Dian Kortleve, Reno Debets, Ron H. J. Mathijssen, Arjen Joosse, Marco W. J. Schreurs et Astrid A. M. Van der Veldt. « Suitability of tumor-associated antibodies as predictive biomarker for response to immune checkpoint inhibitors in patients with melanoma : a short report ». Journal for ImmunoTherapy of Cancer 11, n^o 2 (février 2023) : e006467. http://dx.doi.org/10.1136/jitc-2022-006467.

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In 2019, Fässleret alshowed in this journal that the presence of tumor-associated antibodies correlated with response to immune checkpoint inhibitor treatment in patients with metastatic melanoma. The results of this study suggested that tumor-associated antibodies directed against melanocyte-differentiation antigens and the cancer-germline antigen NY-ESO-1 should be further investigated as candidate biomarkers for response to immune checkpoint inhibitors. The aim of the current study was to validate and extend these previous findings. Therefore, we examined the correlation between serum levels of tumor-associated antibodies and tumor response after treatment with immune checkpoint inhibitors in patients with metastatic melanoma.All patients included in this prospective study were diagnosed with advanced stage melanoma and treated with nivolumab or pembrolizumab monotherapy. Blood samples were collected before and during treatment. Serum levels of tumor-associated antibodies against the melanocyte differentiation antigen Melan-A and the cancer germline antigens NY-ESO-1, MAGE-C2, MAGE-A6 and ROPN1B were measured at baseline and during treatment. Differences between responders and non-responders were assessed using the Mann-Whitney U-test, and differences between different overall survival categories with the Kruskal-Wallis test. P values ≤0.05 were considered significant.Serum samples of 58 patients with advanced melanoma with long-term follow-up (>3 years) were collected. In contrast to the findings of Fässleret al, for all antibodies tested, we found no significant differences between serum levels of responders and non-responders before or during treatment with immune checkpoint inhibitors. In addition, no significant differences were found in serum levels of tumor-associated antibodies for different overall survival groups.Although our study included a larger and more mature cohort of patients with longer follow-up, we could not externally validate the findings of Fässleret al. In addition, we were not able to identify other cancer germline antigens as predictive biomarkers of response to immune checkpoint inhibitors in patients advanced melanoma. Based on the results of the present study, clinical applicability of tumor-associated antibodies directed against tumor antigens as predictive biomarkers for immune checkpoint inhibitors in patients with advanced melanoma is not feasible.

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Azouz, Nurit P., Mario A. Ynga-Durand, Julie M. Caldwell, Ayushi Jain, Mark Rochman, Demetria M. Fischesser, Leanne M. Ray et al. « The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses ». Science Translational Medicine 10, n^o 444 (6 juin 2018) : eaap9736. http://dx.doi.org/10.1126/scitranslmed.aap9736.

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Loss of barrier integrity has an important role in eliciting type 2 immune responses, yet the molecular events that initiate and connect this with allergic inflammation remain unclear. We reveal an endogenous, homeostatic mechanism that controls barrier function and inflammatory responses in esophageal allergic inflammation. We show that a serine protease inhibitor, SPINK7 (serine peptidase inhibitor, kazal type 7), is part of the differentiation program of human esophageal epithelium and that SPINK7 depletion occurs in a human allergic, esophageal condition termed eosinophilic esophagitis. Experimental manipulation strategies reducing SPINK7 in an esophageal epithelial progenitor cell line and primary esophageal epithelial cells were sufficient to induce barrier dysfunction and transcriptional changes characterized by loss of cellular differentiation and altered gene expression known to stimulate allergic responses (for example, FLG and SPINK5). Epithelial silencing of SPINK7 promoted production of proinflammatory cytokines including thymic stromal lymphopoietin (TSLP). Loss of SPINK7 increased the activity of urokinase plasminogen-type activator (uPA), which in turn had the capacity to promote uPA receptor–dependent eosinophil activation. Treatment of epithelial cells with the broad-spectrum antiserine protease, α1 antitrypsin, reversed the pathologic features associated with SPINK7 silencing. The relevance of this pathway in vivo was supported by finding genetic epistasis between variants in TSLP and the uPA-encoding gene, PLAU. We propose that the endogenous balance between SPINK7 and its target proteases is a key checkpoint in regulating mucosal differentiation, barrier function, and inflammatory responses and that protein replacement with antiproteases may be therapeutic for select allergic diseases.

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Smith, Lucas R., Jerome Irianto, Yuntao Xia, Charlotte R. Pfeifer et Dennis E. Discher. « Constricted migration modulates stem cell differentiation ». Molecular Biology of the Cell 30, n^o 16 (22 juillet 2019) : 1985–99. http://dx.doi.org/10.1091/mbc.e19-02-0090.

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Tissue regeneration at an injured site depends on proliferation, migration, and differentiation of resident stem or progenitor cells, but solid tissues are often sufficiently dense and constricting that nuclei are highly stressed by migration. In this study, constricted migration of myoblastic cell types and mesenchymal stem cells (MSCs) increases nuclear rupture, increases DNA damage, and modulates differentiation. Fewer myoblasts fuse into regenerating muscle in vivo after constricted migration in vitro, and myodifferentiation in vitro is likewise suppressed. Myosin II inhibition rescues rupture and DNA damage, implicating nuclear forces, while mitosis and the cell cycle are suppressed by constricted migration, consistent with a checkpoint. Although perturbed proliferation fails to explain defective differentiation, nuclear rupture mislocalizes differentiation-relevant MyoD and KU80 (a DNA repair factor), with nuclear entry of the DNA-binding factor cGAS. Human MSCs exhibit similar damage, but osteogenesis increases—which is relevant to bone and to calcified fibrotic tissues, including diseased muscle. Tissue repair can thus be modulated up or down by the curvature of pores through which stem cells squeeze.

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Miao, Tizong, Alistair L. J. Symonds, Randeep Singh, Janine D. Symonds, Ane Ogbe, Becky Omodho, Bo Zhu, Suling Li et Ping Wang. « Egr2 and 3 control adaptive immune responses by temporally uncoupling expansion from T cell differentiation ». Journal of Experimental Medicine 214, n^o 6 (9 mai 2017) : 1787–808. http://dx.doi.org/10.1084/jem.20160553.

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Egr2 and 3 are important for maintaining immune homeostasis. Here we define a fundamental function of Egr2 and 3 operating as a checkpoint that controls the transition between clonal expansion and differentiation of effector T cells. Egr2 and 3 deficiency resulted in defective clonal expansion but hyperactivation and excessive differentiation of T cells in response to viral infection. Conversely, sustained Egr2 expression enhanced expansion but severely impaired effector differentiation. Egr2 bound to and controlled the expression of genes regulating proliferation (Myc and Myb) and differentiation repressors (Bcl6, Id3), while repressing transcription factors required for effector function (Zeb2, RORa, RORc, and Bhlhe40). Egr2 and 3 expression in T cells was regulated reciprocally by antigen and IFNγ, providing a mechanism for adjusting proliferation and differentiation of individual T cells. Thus, Egr2 and 3 are upstream regulators of effector CD4 and CD8 T cells that are essential for optimal responses with limited immunopathology.

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Lapenta, Caterina, Lucia Gabriele et Stefano Maria Santini. « IFN-Alpha-Mediated Differentiation of Dendritic Cells for Cancer Immunotherapy : Advances and Perspectives ». Vaccines 8, n^o 4 (19 octobre 2020) : 617. http://dx.doi.org/10.3390/vaccines8040617.

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The past decade has seen tremendous developments in novel cancer therapies through targeting immune-checkpoint molecules. However, since increasing the presentation of tumor antigens remains one of the major issues for eliciting a strong antitumor immune response, dendritic cells (DC) still hold a great potential for the development of cancer immunotherapy. A considerable body of evidence clearly demonstrates the importance of the interactions of type I IFN with the immune system for the generation of a durable antitumor response through its effects on DC. Actually, highly active DC can be rapidly generated from blood monocytes in vitro in the presence of IFN-α (IFN-DC), suitable for therapeutic vaccination of cancer patients. Here we review how type I IFN can promote the ex vivo differentiation of human DC and orientate DC functions towards the priming and expansion of protective antitumor immune responses. New epigenetic elements of control on activation of the type I IFN signal will be highlighted. We also review a few clinical trials exploiting IFN-DC in cancer vaccination and discuss how IFN-DC could be exploited for the design of effective strategies of cancer immunotherapy as a monotherapy or in combination with immune-checkpoint inhibitors or immunomodulatory drugs.

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Kim, Young Jae, Chong Hyun Won, Mi Woo Lee, Jee Ho Choi, Sung Eun Chang et Woo Jin Lee. « Correlation Between Tumor-Associated Macrophage and Immune Checkpoint Molecule Expression and Its Prognostic Significance in Cutaneous Melanoma ». Journal of Clinical Medicine 9, n^o 8 (3 août 2020) : 2500. http://dx.doi.org/10.3390/jcm9082500.

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The association between tumor-associated macrophages (TAMs) and the expression of immune checkpoint molecules has not been well described in cutaneous melanoma. We evaluated the correlations between the expression of markers of TAMs, cluster of differentiation 163 (CD163), and immune checkpoint molecules, programmed cell death protein-1 (PD-1), and lymphocyte activating gene-3 (LAG-3). We also determined their relationships with the clinicopathological features and disease outcomes in melanoma. Diagnostic tissues collected from melanoma patients were evaluated using immunohistochemistry for CD163, PD-1, and LAG-3 expression. CD163 expression positively correlated with PD-1 and LAG-3 expression. High expression of both CD163 and PD-1 expressions was significantly associated with negative prognostic factors and worse prognosis than high expression of the single markers. High co-expression of CD163 and LAG-3 was associated with poor clinicopathological indexes of melanoma and worse survival compared to the high expression of the single markers. The expression of immune checkpoint molecules PD-1 and LAG-3 positively correlated with the M2-TAM density in melanoma tissue. Simultaneous high M2-TAM density and immune checkpoint molecules expression acted as independent poor prognostic factors in cutaneous melanoma.

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Li, Jia, et Yuan Zhuang. « Double knockout of Id2 & ; Id3 in developing T cells promotes the development of CD4-CD8- αβ T cell (63.3) ». Journal of Immunology 188, n^o 1_Supplement (1 mai 2012) : 63.3. http://dx.doi.org/10.4049/jimmunol.188.supp.63.3.

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Abstract αβ T cell development is regulated by sequential rearrangement and expression of TCRβ and TCRα genes at the DN (CD4-CD8-) and DP (CD4+CD8+) stage, respectively. Expression of TCRβ paired with preTα at the DN stage leads to αβ lineage commitment and differentiation into the DP stage. DP cells undergo TCRα gene rearrangement, resulting in expression and the selection of functional αβTCR. Id3 has been shown to be an important sensor downstream of both preTCR and TCR signals. However, Id3 knockout only leads to a partial block in αβ lineage development, suggesting functional compensation from other Id proteins. To further investigate functions of Id proteins at the preTCR and TCR checkpoints, we simultaneously deleted Id3 and the structurally and functionally related Id2 gene at the early DN stage of T cell development. We find that removal of Id2 and Id3 failed to block T cell development at the preTCR checkpoint although imposed a strong block at the TCR checkpoint. Furthermore, deletion of both Id2 and Id3 promoted development of an aberrant population of αβ T cells that bear DN (CD4-CD8-) phenotype. This genetic system revealed a novel function of Id proteins in regulation of alternative αβ lineages during T cell development. We will present the latest information on characterization of this CD4-CD8- αβ T cell lineage associated with Id2 and Id3 disruption in developing T cells.

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Shi, Lewis Z., Ruoning Wang, Gonghua Huang, Peter Vogel, Geoffrey Neale, Douglas R. Green et Hongbo Chi. « HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells ». Journal of Experimental Medicine 208, n^o 7 (27 juin 2011) : 1367–76. http://dx.doi.org/10.1084/jem.20110278.

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Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg cells) and controls cell fate determination. TH17 but not Treg cell–inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1α–dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1α resulted in diminished TH17 development but enhanced Treg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.

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Roy, Lydia, Philippe Coullin, Natacha Vitrat, Raymond Hellio, Najet Debili, Jasminder Weinstein, Alain Bernheim et William Vainchenker. « Asymmetrical segregation of chromosomes with a normal metaphase/anaphase checkpoint in polyploid megakaryocytes ». Blood 97, n^o 8 (15 avril 2001) : 2238–47. http://dx.doi.org/10.1182/blood.v97.8.2238.

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Abstract During differentiation, megakaryocytes increase ploidy through a process called endomitosis, whose mechanisms remain unknown. As it corresponds to abortive mitosis at anaphase and is associated with a multipolar spindle, investigation of chromosome segregation may help to better understand this cell-cycle abnormality. To examine this variation, a new method was developed to combine primed in situ labeling to label centromeres of one chromosome category and immunostaining of tubulin. Human megakaryocytes were obtained from normal bone marrow culture. By confocal microscopy, this study demonstrates an asymmetrical distribution of chromosomes (1 or 7) either between the spindle poles at anaphase stage of endomitosis and between the different lobes of interphase megakaryocyte nuclei. The metaphase/anaphase checkpoint appears normal on the evidence that under nocodazole treatment megakaryocytes progressively accumulate in pseudo-metaphase, without spontaneous escape from this blockage. Immunostaining of p55CDC/hCDC20 with similar kinetochore localization and dynamics as during normal mitosis confirms this result. HCdh1 was also expressed in megakaryocytes, and its main target, cyclin B1, was normally degraded at anaphase, suggesting that the hCdh1-anaphase–promoting complex checkpoint was also functional. This study found the explanation for these unexpected results of an asymmetrical segregation coupled to normal checkpoints by careful analysis of multipolar endomitotic spindles: whereas each aster is connected to more than one other aster, one chromosome may segregate symmetrically between 2 spindle poles and still show asymmetrical segregation when the entire complex spindle is considered.

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